Project Summary/Abstract Obesity is associated with increased cardiovascular morbidity and mortality, partly through the development of high blood pressure (hypertension). However, the molecular basis for the relationship between obesity and hypertension remains ill defined. Aberrant leptin action and leptin receptor (LepR) signaling has emerged as an important mechanism underlying obesity-associated hypertension. Leptin is an adipocyte-derived hormone involved in the regulation of energy homeostasis through its action in the brain to suppress food intake and increase energy expenditure. Additionally, leptin has been implicated in the control of blood pressure via regulation of sympathetic nerve activity (SNA) with pathophysiological implications in obesity-induced hypertension. In the brain, the LepR is known to activate multiple intracellular signaling pathways which are differentially involved in mediating the various physiological effects of leptin. Of note, mammalian target of rapamycin complex 1 (mTORC1, composed of multiple subunits including raptor (regulatory associated protein of mTOR) has emerged as a key molecular hub underlying the pressor and sympathetic actions of leptin. However, the specific neuronal population(s) in which mTORC1 mediates these effects of leptin are not known. My preliminary data and published work suggest that proopiomelanocortin (POMC) neurons are critically involved in mediating the renal sympathoexcitatory and hypertensive effects of leptin pointing to these neurons as a potential candidate for the locus of mTORC1-mediated pressor and sympathetic actions of leptin. Thus, I hypothesize that mTORC1 signaling in POMC neurons mediates the effects of leptin on blood pressure and SNA. To test this hypothesis, I developed a genetically modified mouse model in which raptor, a critical subunit of mTORC1, is conditionally deleted in POMC neurons (POMCCrexRaptorfl/fl mice). I will perform a series of experiments to characterize the blood pressure and regional SNA responses to leptin in these mice to define the role of mTORC1 in POMC neurons in mediating these processes.